Oxymorphone controlled release formulations

ABSTRACT

The invention pertains to a method of relieving pain by administering a controlled release pharmaceutical tablet containing oxymorphone which produces a mean minimum blood plasma level 12 to 24 hours after dosing, as well as the tablet producing the sustained pain relief.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/190,192 filed Jul. 3, 2002 and claims priority to U.S. ProvisionalPatent Application Ser. Nos. 60/329,445 filed Oct. 15, 2001, 60/329,432filed Oct. 15, 2001, 60/303,357 filed Jul. 6, 2001, and 60/329,444 filedOct. 15, 2001, which are incorporated herein by reference to the extentpermitted by law.

BACKGROUND OF THE INVENTION

Pain is the most frequently reported symptom and it is a common clinicalproblem which confronts the clinician. Many millions of people in theUSA suffer from severe pain that, according to numerous recent reports,is chronically undertreated or inappropriately managed. The clinicalusefulness of the analgesic properties of opioids has been recognizedfor centuries, and morphine and its derivatives have been widelyemployed for analgesia for decades in a variety of clinical pain states.

Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is asemi-synthetic phenanthrene-derivative opioid agonist, widely used inthe treatment of acute and chronic pain, with analgesic efficacycomparable to other opioid analgesics. Oxymorphone is currently marketedas an injection (1 mg/ml in 1 ml ampules; 1.5 mg/ml in 1 ml ampules; 1.5mg/ml in 10 ml multiple dose vials) for intramuscular, subcutaneous, andintravenous administration, and as 5 mg rectal suppositories. At onetime, 2 mg, 5 mg and 10 mg oral immediate release (IR) tabletformulations of oxymorphone HCl were marketed. Oxymorphone HCl ismetabolized principally in the liver and undergoes conjugation withglucuronic acid and reduction to 6-alpha- and beta-hydroxy epimers.

An important goal of analgesic therapy is to achieve continuous reliefof chronic pain. Regular administration of an analgesic is generallyrequired to ensure that the next dose is given before the effects of theprevious dose have worn off. Compliance with opioids increases as therequired dosing frequency decreases. Non-compliance results insuboptimal pain control and poor quality of life outcomes. (Ferrell B etal. Effects of controlled-release morphine on quality of life for cancerpain. Oncol. Nur. Forum 1989; 4:521-26). Scheduled, rather than “asneeded” administration of opioids is currently recommended in guidelinesfor their use in chronic non-malignant pain. Unfortunately, evidencefrom prior clinical trials and clinical experience suggests that theshort duration of action of immediate release oxymorphone wouldnecessitate administration every 4-6 hours in order to maintain optimallevels of analgesia in chronic pain. A controlled release formulationwhich would allow less frequent dosing of oxymorphone would be useful inpain management.

For instance, a controlled release formulation of morphine has beendemonstrated to provide patients fewer interruptions in sleep, reduceddependence on caregivers, improved compliance, enhanced quality of lifeoutcomes, and increased control over the management of pain. Inaddition, the controlled release formulation of morphine was reported toprovide more constant plasma concentration and clinical effects, lessfrequent peak to trough fluctuations, reduced dosing frequency, andpossibly fewer side effects. (Thirlwell M P et al., Pharmacokinetics andclinical efficacy of oral morphine solution and controlled-releasemorphine tablets in cancer patients. Cancer 1989; 63:2275-83; GoughnourB R et al., Analgesic response to single and multiple doses ofcontrolled-release morphine tablets and morphine oral solution in cancerpatients. Cancer 1989; 63:2294-97; Ferrell B. et al., Effects ofcontrolled-release morphine on quality of life for cancer pain. Oncol.Nur. Forum 1989; 4:521-26.

There are two factors associated with the metabolism of some drugs thatmay present problems for their use in controlled release systems. One isthe ability of the drug to induce or inhibit enzyme synthesis, which mayresult in a fluctuating drug blood plasma level with chronic dosing. Theother is a fluctuating drug blood level due to intestinal (or othertissue) metabolism or through a hepatic first-pass effect.

Oxymorphone is metabolized principally in the liver, resulting in anoral bioavailability of about 10%. Evidence from clinical experiencesuggests that the short duration of action of immediate releaseoxymorphone necessitates a four hour dosing schedule to maintain optimallevels of analgesia. It would be useful to clinicians and patients aliketo have controlled release dosage forms of oxymorphone to use to treatpain and a method of treating pain using the dosage forms.

SUMMARY OF THE INVENTION

The present invention provides methods for relieving pain byadministering a controlled release pharmaceutical tablet containingoxymorphone which produces at least a predetermined minimum blood plasmalevel for at least 12 hours after dosing, as well as tablets thatproduce the sustained pain relief over this time period.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a pharmacokinetic profile for 6-hydroxy oxymorphone with PIDscores.

FIG. 2 is a pharmacokinetic profile for oxymorphone with PID scores.

FIG. 3 is a pharmacokinetic profile for 6-hydroxy oxymorphone withcategorical pain scores.

FIG. 4 is a pharmacokinetic profile for oxymorphone with categoricalpain scores.

FIG. 5 is a graph of the mean blood plasma concentration of oxymorphoneversus time for clinical study 1.

FIG. 6 is a graph of the mean blood plasma concentration of oxymorphoneversus time for clinical study 2.

FIG. 7 is a graph of the mean blood plasma concentration of oxymorphoneversus time for clinical study 3.

FIG. 8 is a graph of the mean blood plasma concentration of 6-hydroxyoxymorphone versus time for clinical study 3.

FIG. 9 is a graph of the mean blood plasma concentration of oxymorphonefor immediate and controlled release tablets from a single dose study.

FIG. 10 is a graph of the mean blood plasma concentration of oxymorphonefor immediate and controlled release tablets from a steady state study.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for alleviating pain for 12 to 24hours using a single dose of a pharmaceutical composition by producing ablood plasma level of oxymorphone and/or 6-OH oxymorphone of at least aminimum value for at least 12 hours or more. As used herein, the terms“6-OH oxymorphone” and “6-hydroxy oxymorphone” are interchangeable andrefer to the analog of oxymorphone having an alcohol (hydroxy) moietythat replaces the carboxy moiety found on oxymorphone at the 6-position.

To overcome the difficulties associated with a 4-6 hourly dosingfrequency of oxymorphone, this invention provides an oxymorphonecontrolled release oral solid dosage form, comprising a therapeuticallyeffective amount of oxymorphone or a pharmaceutically acceptable salt ofoxymorphone. It has been found that the decreased rate of release ofoxymorphone from the oral controlled release formulation of thisinvention does not substantially decrease the bioavailability of thedrug as compared to the same dose of a solution of oxymorphoneadministered orally. The bioavailability is sufficiently high and therelease rate is such that a sufficient plasma level of oxymorphoneand/or 6-OH oxymorphone is maintained to allow the controlled releasedosage to be used to treat patients suffering moderate to severe painwith once or twice daily dosing. The dosing form of the presentinvention can also be used with thrice daily dosing.

It is critical when considering the present invention that thedifference between a controlled release tablet and an immediate releaseformulation be fully understood. In classical terms, an immediaterelease formulation releases at least 80% of its active pharmaceuticalingredient within 30 minutes. With reference to the present invention,the definition of an immediate release formulation will be broadenedfurther to include a formulation which releases more than about 80% ofits active pharmaceutical ingredient within 60 minutes in a standard USPPaddle Method dissolution test at 50 rpm in 500 ml media having a pH ofbetween 1.2 and 6.8 at 37° C. “Controlled release” formulations, asreferred to herein, will then encompass any formulations which releaseno more than about 80% of their active pharmaceutical ingredients within60 minutes under the same conditions.

The controlled release dosage form of this invention exhibits adissolution rate in vitro, when measured by USP Paddle Method at 50 rpmin 500 ml media having a pH between 1.2 and 6.8 at 37° C., of about 15%to about 50% by weight oxymorphone released after 1 hour, about 45% toabout 80% by weight oxymorphone released after 4 hours, and at leastabout 80% by weight oxymorphone released after 10 hours.

When administered orally to humans, an effective controlled releasedosage form of oxymorphone should exhibit the following in vivocharacteristics: (a) peak plasma level of oxymorphone occurs withinabout 1 to about 8 hours after administration; (b) peak plasma level of6-OH oxymorphone occurs within about 1 to about 8 hours afteradministration; (c) duration of analgesic effect is through about 8 toabout 24 hours after administration; (d) relative oxymorphonebioavailability is in the range of about 0.5 to about 1.5 compared to anorally-administered aqueous solution of oxymorphone; and (e) the ratioof the area under the curve of blood plasma level vs. time for 6-OHoxymorphone compared to oxymorphone is in the range of about 0.5 toabout 1.5. Of course, there is variation of these parameters amongsubjects, depending on the size and weight of the individual subject,the subject's age, individual metabolism differences, and other factors.Indeed, the parameters may vary in an individual from day to day.Accordingly, the parameters set forth above are intended to be meanvalues from a sufficiently large study so as to minimize the effect ofindividual variation in arriving at the values. A convenient method forarriving at such values is by conducting a study in accordance withstandard FDA procedures such as those employed in producing results foruse in a new drug application (or abbreviated new drug application)before the FDA. Any reference to mean values herein, in conjunction withdesired results, refer to results from such a study, or some comparablestudy. Reference to mean values reported herein for studies actuallyconducted are arrived at using standard statistical methods as would beemployed by one skilled in the art of pharmaceutical formulation andtesting for regulatory approval.

In one specific embodiment of the controlled release matrix form of theinvention, the oxymorphone or salt of oxymorphone is dispersed in acontrolled release delivery system that comprises a hydrophilic materialwhich, upon exposure to gastrointestinal fluid, forms a gel matrix thatreleases oxymorphone at a controlled rate. The rate of release ofoxymorphone from the matrix depends on the drug's partition coefficientbetween components of the matrix and the aqueous phase within thegastrointestinal tract. In a preferred form of this embodiment, thehydrophilic material of the controlled release delivery system comprisesa mixture of a heteropolysaccharide gum and an agent capable ofcross-linking the heteropolysaccharide in presence of gastrointestinalfluid. The controlled release delivery system may also comprise awater-soluble pharmaceutical diluent mixed with the hydrophilicmaterial. Preferably, the cross-linking agent is a homopolysaccharidegum and the inert pharmaceutical diluent is a monosaccharide, adisaccharide, or a polyhydric alcohol, or a mixture thereof.

In a specific preferred embodiment, the appropriate blood plasma levelsof oxymorphone and 6-hydroxy oxymorphone are achieved using oxymorphonein the form of oxymorphone hydrochloride, wherein the weight ratio ofheteropolysaccharide to homopolysaccharide is in the range of about 1:3to about 3:1, the weight ratio of heteropolysaccharide to diluent is inthe range of about 1:8 to about 8:1, and the weight ratio ofheteropolysaccharide to oxymorphone hydrochloride is in the range ofabout 10:1 to about 1:10. A preferred heteropolysaccharide is xanthangum and a preferred homopolysaccharide is locust bean gum. The dosageform also comprises a cationic cross-linking agent and a hydrophobicpolymer. In the preferred embodiment, the dosage form is a tabletcontaining about 5 mg to about 80 mg of oxymorphone hydrochloride. In amost preferred embodiment, the tablet contains about 20 mg oxymorphonehydrochloride.

The invention includes a method which comprises achieving appropriateblood plasma levels of drug while providing extended pain relief byadministering one to three times per day to a patient suffering moderateto severe, acute or chronic pain, an oxymorphone controlled release oralsolid dosage form of the invention in an amount sufficient to alleviatethe pain for a period of about 8 hours to about 24 hours. This type andintensity of pain is often associated with cancer, autoimmune diseases,infections, surgical and accidental traumas and osteoarthritis.

The invention also includes a method of making an oxymorphone controlledrelease oral solid dosage form of the invention which comprises mixingparticles of oxymorphone or a pharmaceutically acceptable salt ofoxymorphone with granules comprising the controlled release deliverysystem, preferably followed by directly compressing the mixture to formtablets.

Pharmaceutically acceptable salts of oxymorphone which can be used inthis invention include salts with the inorganic and organic acids whichare commonly used to produce nontoxic salts of medicinal agents.Illustrative examples would be those salts formed by mixing oxymorphonewith hydrochloric, sulfuric, nitric, phosphoric, phosphorous,hydrobromic, maleric, malic, ascorbic, citric or tartaric, pamoic,lauric, stearic, palmitic, oleic, myristic, lauryl sulfuric,naphthylenesulfonic, linoleic or linolenic acid, and the like. Thehydrochloride salt is preferred.

It has now been found that 6-OH oxymorphone, which is one of themetabolites of oxymorphone, may play a role in alleviating pain. Whenoxymorphone is ingested, part of the dosage gets into the bloodstream toprovide pain relief, while another part is metabolized to 6-OHoxymorphone. This metabolite then enters the bloodstream to providefurther pain relief. Thus it is believed that both the oxymorphone and6-hydroxyoxymorphone levels are important to pain relief.

The effectiveness of oxymorphone and 6-hydroxyoxymorphone at relievingpain and the pharmacokinetics of a single dose of oxymorphone werestudied. The blood plasma levels of both oxymorphone and6-hydroxyoxymorphone were measured in patients after a single dose ofoxymorphone was administered. Similarly, the pain levels in patientswere measured after a single administration of oxymorphone to determinethe effective duration of pain relief from a single dose. FIGS. 1-2 showthe results of these tests, comparing pain levels to oxymorphone and6-hydroxy oxymorphone levels.

For these tests, pain was measured using a Visual Analog Scale (VAS) ora Categorical Scale. The VAS scales consisted of a horizontal line, 100mm in length. The left-hand end of the scale (0 mm) was marked with thedescriptor “No Pain” and the right-hand end of the scale (100 mm) wasmarked with the descriptor “Extreme Pain”. Patients indicated theirlevel of pain by making a vertical mark on the line. The VAS score wasequal to the distance (in mm) from the left-hand end of the scale to thepatient's mark. For the categorical scale, patients completed thefollowing statement, “My pain at this time is” using the scale None=0,Mild=1, Moderate=2, or Severe=3.

As can be seen from these figures, there is a correlation between painrelief and both oxymorphone and 6-hydroxyoxymorphone levels. As theblood plasma levels of oxymorphone and 6-hydroxyoxymorphone increase,pain decreases (and pain intensity difference and pain reliefincreases). Thus, to the patient, it is the level of oxymorphone and6-hydroxyoxymorphone in the blood plasma which is most important.Further it is these levels which dictate the efficacy of the dosageform. A dosage form which maintains a sufficiently high level ofoxymorphone or 6-hydroxyoxymorphone for a longer period need not beadministered frequently. Such a result is accomplished by embodiments ofthe present invention.

The oxymorphone controlled release oral solid dosage form of thisinvention can be made using any of several different techniques forproducing controlled release oral solid dosage forms of opioidanalgesics.

In one embodiment, a core comprising oxymorphone or oxymorphone salt iscoated with a controlled release film which comprises a water insolublematerial and which upon exposure to gastrointestinal fluid releasesoxymorphone from the core at a controlled rate. In a second embodiment,the oxymorphone or oxymorphone salt is dispersed in a controlled releasedelivery system that comprises a hydrophilic material which uponexposure to gastrointestinal fluid forms a gel matrix that releasesoxymorphone at a controlled rate. A third embodiment is a combination ofthe first two: a controlled release matrix coated with a controlledrelease film. In a fourth embodiment the oxymorphone is incorporatedinto an osmotic pump. In any of these embodiments, the dosage form canbe a tablet, a plurality of granules in a capsule, or other suitableform, and can contain lubricants, colorants, diluents, and otherconventional ingredients.

Osmotic Pump

An osmotic pump comprises a shell defining an interior compartment andhaving an outlet passing through the shell. The interior compartmentcontains the active pharmaceutical ingredient. Generally the activepharmaceutical ingredient is mixed with excipients or other compositionssuch as a polyalkylene. The shell is generally made, at least in part,from a material (such as cellulose acetate) permeable to the liquid ofthe environment where the pump will be used, usually stomach acid. Onceingested, the pump operates when liquid diffuses through the shell ofthe pump. The liquid dissolves the composition to produce a saturatedsituation. As more liquid diffuses into the pump, the saturated solutioncontaining the pharmaceutical is expelled from the pump through theoutlet. This produces a nearly constant release of active ingredient, inthe present case, oxymorphone.

Controlled Release Coating

In this embodiment, a core comprising oxymorphone or oxymorphone salt iscoated with a controlled release film which comprises a water insolublematerial. The film can be applied by spraying an aqueous dispersion ofthe water insoluble material onto the core. Suitable water insolublematerials include alkyl celluloses, acrylic polymers, waxes (alone or inadmixture with fatty alcohols), shellac and zein. The aqueousdispersions of alkyl celluloses and acrylic polymers preferably containa plasticizer such as triethyl citrate, dibutyl phthalate, propyleneglycol, and polyethylene glycol. The film coat can contain awater-soluble material such as polyvinylpyrrolidone (PVP) orhydroxypropylmethylcellulose (HPMC).

The core can be a granule made, for example, by wet granulation of mixedpowders of oxymorphone or oxymorphone salt and a binding agent such asHPMC, or by coating an inert bead with oxymorphone or oxymorphone saltand a binding agent such as HPMC, or by spheronising mixed powders ofoxymorphone or oxymorphone salt and a spheronising agent such asmicrocrystalline cellulose. The core can be a tablet made by compressingsuch granules or by compressing a powder comprising oxymorphone oroxymorphone salt.

The in vitro and in vivo release characteristics of this controlledrelease dosage form can be modified by using mixtures of different waterinsoluble and water soluble materials, using different plasticizers,varying the thickness of the controlled release film, includingrelease-modifying agents in the coating, or by providing passagewaysthrough the coating.

Controlled Release Matrix

It is important in the present invention that appropriate blood plasmalevels of oxymorphone and 6-hydroxy oxymorphone be achieved andmaintained for sufficient time to provide pain relief to a patient for aperiod of 12 to 24 hours. The preferred composition for achieving andmaintaining the proper blood plasma levels is a controlled-releasematrix. In this embodiment, the oxymorphone or oxymorphone salt isdispersed in a controlled release delivery system that comprises ahydrophilic material (gelling agent) which upon exposure togastrointestinal fluid forms a gel matrix that releases oxymorphone at acontrolled rate. Such hydrophilic materials include gums, celluloseethers, acrylic resins, and protein-derived materials. Suitablecellulose ethers include hydroxyalkyl celluloses and carboxyalkylcelluloses, especially hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), HPMC, and carboxy methylcellulose (CMC). Suitableacrylic resins include polymers and copolymers of acrylic acid,methacrylic acid, methyl acrylate and methyl methacrylate. Suitable gumsinclude heteropolysaccharide and homopolysaccharide gums, e.g., xanthan,tragacanth, acacia, karaya, alginates, agar, guar, hydroxypropyl guar,carrageenan, and locust bean gums.

Preferably, the controlled release tablet of the present invention isformed from (I) a hydrophilic material comprising (a) aheteropolysaccharide; or (b) a heteropolysaccharide and a cross-linkingagent capable of cross-linking said heteropolysaccharide; or (c) amixture of (a), (b) and a polysaccharide gum; and (II) an inertpharmaceutical filler comprising up to about 80% by weight of thetablet; and (III) oxymorphone.

The term “heteropolysaccharide” as used herein is defined as awater-soluble polysaccharide containing two or more kinds of sugarunits, the heteropolysaccharide having a branched or helicalconfiguration, and having excellent water-wicking properties and immensethickening properties.

A preferred heteropolysaccharide is xanthan gum, which is a highmolecular weight (>10⁶) heteropolysaccharide. Other preferredheteropolysaccharides include derivatives of xanthan gum, such asdeacylated xanthan gum, the carboxymethyl ether, and the propyleneglycol ester.

The cross linking agents used in the controlled release embodiment ofthe present invention which are capable of cross-linking with theheteropolysaccharide include homopolysaccharide gums such as thegalactomannans, i.e., polysaccharides which are composed solely ofmannose and galactose. Galactomannans which have higher proportions ofunsubstituted mannose regions have been found to achieve moreinteraction with the heteropolysaccharide. Locust bean gum, which has ahigher ratio of mannose to the galactose, is especially preferred ascompared to other galactomannans such as guar and hydroxypropyl guar.

Preferably, the ratio of heteropolysaccharide to homopolysaccharide isin the range of about 1:9 to about 9:1, preferably about 1:3 to about3:1. Most preferably, the ratio of xanthan gum to polysaccharidematerial (i.e., locust bean gum, etc.) is preferably about 1:1.

In addition to the hydrophilic material, the controlled release deliverysystem can also contain an inert pharmaceutical diluent such as amonosaccharide, a disaccharide, a polyhydric alcohol and mixturesthereof. The ratio of diluent to hydrophilic matrix-forming material isgenerally in the range of about 1:3 to about 3:1.

The controlled release properties of the controlled release embodimentof the present invention may be optimized when the ratio ofheteropolysaccharide gum to homopolysaccharide material is about 1:1,although heteropolysaccharide gum in an amount of from about 20 to about80% or more by weight of the heterodisperse polysaccharide materialprovides an acceptable slow release product. The combination of anyhomopolysaccharide gums known to produce a synergistic effect whenexposed to aqueous solutions may be used in accordance with the presentinvention. It is also possible that the type of synergism which ispresent with regard to the gum combination of the present inventioncould also occur between two homogeneous or two heteropolysaccharides.Other acceptable gelling agents which may be used in the presentinvention include those gelling agents well-known in the art. Examplesinclude vegetable gums such as alginates, carrageenan, pectin, guar gum,xanthan gum, modified starch, hydroxypropylmethylcellulose,methylcellulose, and other cellulosic materials such as sodiumcarboxymethylcellulose and hydroxypropyl cellulose. This list is notmeant to be exclusive.

The combination of xanthan gum with locust bean gum with or without theother homopolysaccharide gums is an especially preferred gelling agent.The chemistry of certain of the ingredients comprising the excipients ofthe present invention such as xanthan gum is such that the excipientsare considered to be self-buffering agents which are substantiallyinsensitive to the solubility of the medicament and likewise insensitiveto the pH changes along the length of the gastrointestinal tract.

The inert filler of the sustained release excipient preferably comprisesa pharmaceutically acceptable saccharide, including a monosaccharide, adisaccharide, or a polyhydric alcohol, and/or mixtures of any of theforegoing. Examples of suitable inert pharmaceutical fillers includesucrose, dextrose, lactose, microcrystalline cellulose, fructose,xylitol, sorbitol, mixtures thereof and the like. However, it ispreferred that a soluble pharmaceutical filler such as lactose,dextrose, sucrose, or mixtures thereof be used.

The cationic cross-linking agent which is optionally used in conjunctionwith the controlled release embodiment of the present invention may bemonovalent or multivalent metal cations. The preferred salts are theinorganic salts, including various alkali metal and/or alkaline earthmetal sulfates, chlorides, borates, bromides, citrates, acetates,lactates, etc. Specific examples of suitable cationic cross-linkingagents include calcium sulfate, sodium chloride, potassium sulfate,sodium carbonate, lithium chloride, tripotassium phosphate, sodiumborate, potassium bromide, potassium fluoride, sodium bicarbonate,calcium chloride, magnesium chloride, sodium citrate, sodium acetate,calcium lactate, magnesium sulfate and sodium fluoride. Multivalentmetal cations may also be utilized. However, the preferred cationiccross-linking agents are bivalent. Particularly preferred salts arecalcium sulfate and sodium chloride. The cationic cross-linking agentsof the present invention are added in an amount effective to obtain adesirable increased gel strength due to the cross-linking of the gellingagent (e.g., the heteropolysaccharide and homopolysaccharide gums). Inpreferred embodiments, the cationic cross-linking agent is included inthe sustained release excipient of the present invention in an amountfrom about 1 to about 20% by weight of the sustained release excipient,and in an amount about 0.5% to about 16% by weight of the final dosageform.

In the controlled release embodiments of the present invention, thesustained release excipient comprises from about 10 to about 99% byweight of a gelling agent comprising a heteropolysaccharide gum and ahomopolysaccharide gum, from about 1 to about 20% by weight of acationic crosslinking agent, and from about 0 to about 89% by weight ofan inert pharmaceutical diluent. In other embodiments, the sustainedrelease excipient comprises from about 10 to about 75% gelling agent,from about 2 to about 15% cationic crosslinking agent, and from about 30to about 75% inert diluent. In yet other embodiments, the sustainedrelease excipient comprises from about 30 to about 75% gelling agent,from about 5 to about 10% cationic cross-linking agent, and from about15 to about 65% inert diluent.

The sustained release excipient used in this embodiment of the presentinvention (with or without the optional cationic cross-linking agent)may be further modified by incorporation of a hydrophobic material whichslows the hydration of the gums without disrupting the hydrophilicmatrix. This is accomplished in preferred embodiments of the presentinvention by granulating the sustained release excipient with thesolution or dispersion of a hydrophobic material prior to theincorporation of the medicament. The hydrophobic polymer may be selectedfrom an alkylcellulose such as ethylcellulose, other hydrophobiccellulosic materials, polymers or copolymers derived from acrylic ormethacrylic acid esters, copolymers of acrylic and methacrylic acidesters, zein, waxes, shellac, hydrogenated vegetable oils, and any otherpharmaceutically acceptable hydrophobic material known to those skilledin the art. The amount of hydrophobic material incorporated into thesustained release excipient is that which is effective to slow thehydration of the gums without disrupting the hydrophilic matrix formedupon exposure to an environmental fluid. In certain preferredembodiments of the present invention, the hydrophobic material isincluded in the sustained release excipient in an amount from about 1 toabout 20% by weight. The solvent for the hydrophobic material may be anaqueous or organic solvent, or mixtures thereof.

Examples of commercially available alkylcelluloses are Aquacoat coating(aqueous dispersion of ethylcellulose available from FMC ofPhiladelphia, Pa.) and Surelease coating (aqueous dispersion ofethylcellulose available from Colorcon of West Point, Pa.). Examples ofcommercially available acrylic polymers suitable for use as thehydrophobic material include Eudragit RS and RL polymers (copolymers ofacrylic and methacrylic acid esters having a low content (e.g., 1:20 or1:40) of quaternary ammonium compounds available from Rohm America ofPiscataway, N.J.).

The controlled release matrix useful in the present invention may alsocontain a cationic cross-linking agent such as calcium sulfate in anamount sufficient to cross-link the gelling agent and increase the gelstrength, and an inert hydrophobic material such as ethyl cellulose inan amount sufficient to slow the hydration of the hydrophilic materialwithout disrupting it. Preferably, the controlled release deliverysystem is prepared as a pre-manufactured granulation.

EXAMPLES Example 1

Two controlled release delivery systems are prepared by dry blendingxanthan gum, locust bean gum, calcium sulfate dehydrate, and dextrose ina high speed mixed/granulator for 3 minutes. A slurry is prepared bymixing ethyl cellulose with alcohol. While running choppers/impellers,the slurry is added to the dry blended mixture, and granulated foranother 3 minutes. The granulation is then dried to a LOD (loss ondrying) of less than about 10% by weight. The granulation is then milledusing 20 mesh screen. The relative quantities of the ingredients arelisted in the table below.

TABLE 1 Controlled Release Delivery System Formulation 1 Formulation 2Excipient (%) (%) Locust Bean Gum, FCC 25.0 30.0 Xanthan Gum, NF 25.030.0 Dextrose, USP 35.0 40.0 Calcium Sulfate Dihydrate, NF 10.0 0.0Ethylcellulose, NF 5.0 0.0 Alcohol, SD3A (Anhydrous) (10)¹ (20.0)¹ Total100.0 100.0

A series of tablets containing different amounts of oxymorphonehydrochloride were prepared using the controlled release deliveryFormulation 1 shown in Table 1. The quantities of ingredients per tabletare as listed in the following table.

TABLE 2 Sample Tablets of Differing Strengths Component Amounts inTablet (mg) Oxymorphone HCl, 5 10 20 40 80 USP (mg) Controlled release160 160 160 160 160 delivery system Silicified 20 20 20 20 20microcrystalline cellulose, N.F. Sodium stearyl 2 2 2 2 2 fumarate, NFTotal weight 187 192 202 222 262 Opadry (colored) 7.48 7.68 8.08 8.8810.48 Opadry (clear) 0.94 0.96 1.01 1.11 1.31

Examples 2 and 3

Two batches of 20 mg tablets were prepared as described above, using thecontrolled release delivery system of Formulation 1. One batch wasformulated to provide relatively fast controlled release, the otherbatch was formulated to provide relatively slow controlled release.Compositions of the tablets are shown in the following table.

TABLE 3 Slow and Fast Release Compositions Example 2 Example 3 Example 4Ingredients Slow (mg) Fast (mg) Fast (mg) Oxymorphone HCl, USP 20 20 20Controlled Release Delivery System 360 160 160 SilicifiedMicrocrystalline Cellulose, 20 20 20 NF Sodium stearyl fumarate, NF 4 22 Total weight 404 202 202 Coating (color or clear) 12 12 9

The tablets of Examples 2, 3, and 4 were tested for in vitro releaserate according to USP Procedure Drug Release U.S. Pat. No. 23. Releaserate is a critical variable in attempting to control the blood plasmalevels of oxymorphone and 6-hydroxyoxymorphone in a patient. Results areshown in the following Table 4.

TABLE 4 Release Rates of Slow and Fast Release Tablets Example 2 Example3 Example 4 Time (hr) (Slow Release) (Fast Release) (Fast Release) 0.518.8 21.3 20.1 1 27.8 32.3 31.7 2 40.5 47.4 46.9 3 50.2 58.5 57.9 4 58.166.9 66.3 5 64.7 73.5 74.0 6 70.2 78.6 83.1 8 79.0 86.0 92.0 10 85.390.6 95.8 12 89.8 93.4 97.3 Clinical Studies

Three clinical studies were conducted to assess the bioavailability(rate and extent of absorption) of oxymorphone. Study 1 addressed therelative rates of absorption of controlled release (CR) oxymorphonetablets (of Examples 2 and 3) and oral oxymorphone solution in fastedpatients. Study 2 addressed the relative rates of absorption of CRoxymorphone tablets (of Examples 2 and 3) and oral oxymorphone solutionin fed patients. Study 3 addressed the relative rates of absorption ofCR oxymorphone tablets (of Example 4) and oral oxymorphone solution infed and fasted patients.

The blood plasma levels set forth herein as appropriate to achieve theobjects of the present invention are mean blood plasma levels. As anexample, if the blood plasma level of oxymorphone in a patient 12 hoursafter administration of a tablet is said to be at least 0.5 ng/ml, anyparticular individual may have lower blood plasma levels after 12 hours.However, the mean minimum concentration should meet the limitation setforth. To determine mean parameters, a study should be performed with aminimum of 8 adult subjects, in a manner acceptable for filing anapplication for drug approval with the US Food and Drug Administration.In cases where large fluctuations are found among patients, furthertesting may be necessary to accurately determine mean values.

For all studies, the following procedures were followed, unlessotherwise specified for a particular study.

The subjects were not to consume any alcohol-, caffeine-, orxanthine-containing foods or beverages for 24 hours prior to receivingstudy medication for each study period. Subjects were to be nicotine andtobacco free for at least 6 months prior to enrolling in the study. Inaddition, over-the-counter medications were prohibited 7 days prior todosing and during the study. Prescription medications were not allowed14 days prior to dosing and during the study.

Pharmacokinetic and Statistical Methods

The following pharmacokinetic parameters were computed from the plasmaoxymorphone concentration-time data:

AUC_((0-t)) Area under the drug concentration-time curve from time zeroto the time of the last quantifiable concentration (Ct), calculatedusing linear trapezoidal summation.

AUC_((0-inf)) Area under the drug concentration-time curve from timezero to infinity. AUC_((0-inf))=AUC_((0-t))+Ct/K_(el), where K_(el) isthe terminal elimination rate constant.

AUC₍₀₋₂₄₎ Partial area under the drug concentration-time curve from timezero to 24 hours.

C_(max) Maximum observed drug concentration.

T_(max) Time of the observed maximum drug concentration.

K_(el) Elimination rate constant based on the linear regression of theterminal linear portion of the LN (concentration) time curve.

Terminal elimination rate constants for use in the above calculationswere in turn computed using linear regression of a minimum of three timepoints, at least two of which were consecutive. K_(el) values for whichcorrelation coefficients were less than or equal to 0.8 were notreported in the pharmacokinetic parameter tables or included in thestatistical analysis. Thus AUC_((0-inf)) was also not reported in thesecases.

A parametric (normal-theory) general linear model was applied to each ofthe above parameters (excluding T_(max)), and the LN-transformedparameters C_(max), AUC₍₀₋₂₄₎, AUC_((0-t)), and AUC_((0-inf)).Initially, the analysis of variance (ANOVA) model included the followingfactors: treatment, sequence, subject within sequence, period, andcarryover effect. If carryover effect was not significant, it wasdropped from the model. The sequence effect was tested using the subjectwithin sequence mean square, and all other main effects were testedusing the residual error (error mean square).

Plasma oxymorphone concentrations were listed by subject at eachcollection time and summarized using descriptive statistics.Pharmacokinetic parameters were also listed by subject and summarizedusing descriptive statistics.

Study 1-Two Controlled Release Formulations; Fasted Patients

Healthy volunteers received a single oral dose of 20 mg CR oxymorphonetaken with 240 ml water after a 10-hour fast. Subjects received thetablets of Example 2 (Treatment 1A) or Example 3 (Treatment 1B). Furthersubjects were given a single oral dose of 10 mg/10 ml oxymorphonesolution in 180 ml apple juice followed with 60 ml water (Treatment 1C).The orally dosed solution was used to simulate an immediate release (IR)dose.

This study had a single-center, open-label, randomized, three-waycrossover design using fifteen subjects. Subjects were in a fasted statefollowing a 10-hour overnight fast. There was a 14-day washout intervalbetween the three dose administrations. The subjects were confined tothe clinic during each study period. Subjects receiving Treatment 1Cwere confined for 18 hours and subjects receiving Treatments 1A or 1Bwere confined for 48 hours after dosing. Ten-milliliter blood sampleswere collected during each study period at the 0 hour (predose), and at0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32,36, and 48 hours postdose for subjects receiving Treatment 1A or 1B and0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 10,12, 14, 16, and 18 hours post-dose. The mean plasma concentration ofoxymorphone versus time for each treatment across all subjects is shownin table 5.

TABLE 5 Mean Plasma Concentration vs. Time (ng/ml) Time (hr) Treatment1A Treatment 1B Treatment 1C 0 0.000 0.000 0.0000 0.25 0.9489 0.5 0.29410.4104 1.3016 0.75 1.3264 1 0.5016 0.7334 1.3046 1.25 1.2041 1.5 0.59510.8192 1.0813 1.75 0.9502 2 0.6328 0.7689 0.9055 2.5 0.7161 3 0.57430.7341 0.6689 4 0.5709 0.6647 0.4879 5 0.7656 0.9089 0.4184 6 0.71490.7782 0.3658 7 0.6334 0.6748 0.3464 8 0.5716 0.5890 0.2610 10 0.48340.5144 0.2028 12 0.7333 0.6801 0.2936 14 0.6271 0.6089 0.2083 16 0.49860.4567 0.1661 18 0.4008 0.3674 0.1368 20 0.3405 0.2970 24 0.2736 0.227028 0.3209 0.2805 32 0.2846 0.2272 36 0.2583 0.1903 48 0.0975 0.0792

The results are shown graphically in FIG. 5. In both Table 5 and FIG. 5,the results are normalized to a 20 mg dosage. The immediate releaseliquid of Treatment 1C shows a classical curve, with a high andrelatively narrow peak, followed by an exponential drop in plasmaconcentration. However, the controlled release oxymorphone tabletsexhibit triple peaks in blood plasma concentration. The first peakoccurs (on average) at around 3 hours. The second peak of the mean bloodplasma concentration is higher than the first, occurring around 6-7hours, on average).

Occasionally, in an individual, the first peak is higher than thesecond, although generally this is not the case. This makes it difficultto determine the time to maximum blood plasma concentration (T_(max))because if the first peak is higher than the second, maximum bloodplasma concentration (C_(max)) occurs much earlier (at around 3 hours)than in the usual case where the second peak is highest. Therefore, whenwe refer to the time to peak plasma concentration (T_(max)) unlessotherwise specified, we refer to the time to the second peak. Further,when reference is made to the second peak, we refer to the time or bloodplasma concentration at the point where the blood plasma concentrationbegins to drop the second time. Generally, where the first peak ishigher than the second, the difference in the maximum blood plasmaconcentration at the two peaks is small. Therefore, this difference (ifany) was ignored and the reported C_(max) was the true maximum bloodplasma concentration and not the concentration at the second peak.

TABLE 6 Pharmacokinetic Parameters of Plasma Oxymorphone for Study 1Treatment 1A Treatment 1B Treatment 1C Mean SD Mean SD Mean SD C_(max)0.8956 0.2983 1.0362 0.3080 2.9622 1.0999 T_(max) 7.03 4.10 4.89 3.440.928 0.398 AUC_((0-t)) 17.87 6.140 17.16 6.395 14.24 5.003AUC_((0-inf)) 19.87 6.382 18.96 6.908 16.99 5.830 T_(1/2el) 10.9 2.6811.4 2.88 6.96 4.61 Units: C_(max) in ng/ml, T_(max) in hours, AUC inng * hr/ml, T_(1/2el) in hours.

Relative bioavailability determinations are set forth in Tables 7 and 8.For these calculations, AUC was normalized for all treatments to a 20 mgdose.

TABLE 7 Relative Bioavailability (F_(rel)) Determination Based onAUC_((0–inf)) F_(rel) (1A vs. 1C) F_(rel) (1B vs. 1C) F_(rel) (1A vs.1B) 1.193 .±. 0.203 1.121 .±. 0.211 1.108 .±. 0.152

TABLE 8 Relative Bioavailability Determination Based on AUC_((0–18))F_(rel) (1A vs. 1C) F_(rel) (1B vs. 1C) F_(rel) (1A vs. 1B) 0.733 .±.0.098 0.783 .±. 0.117 0.944 .±. 0.110

Study 2-Two CR Formulations; Fed Patients

Healthy volunteers received a single oral dose of 20 mg CR oxymorphonetaken with 240 ml water in a fed state. Subjects received the tablets ofExample 2 (Treatment 2A) or Example 3 (Treatment 2B). Further subjectswere given a single oral dose of 10 mg/10 ml oxymorphone solution in 180ml apple juice followed with 60 ml water (Treatment 2C). The orallydosed solution was used to simulate an immediate release (IR) dose.

This study had a single-center, open-label, randomized, three-waycrossover design using fifteen subjects. The subjects were in a fedstate, after a 10-hour overnight fast followed by a standardized FDAhigh-fat breakfast. There was a 14-day washout interval between thethree dose administrations. The subjects were confined to the clinicduring each study period. Subjects receiving Treatment 2C were confinedfor 18 hours and subjects receiving Treatments 2A or 2B were confinedfor 48 hours after dosing. Ten-milliliter blood samples were collectedduring each study period at the 0 hour (predose), and at 0.5, 1, 1.5, 2,3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, and 48 hourspostdose for subjects receiving Treatment 2A or 2B and 0, 0.25, 0.5,0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and18 hours postdose. The mean plasma concentration of oxymorphone versustime for each treatment across all subjects is shown in table 9.

TABLE 9 Mean Plasma Concentration vs. Time (ng/ml) Time (hr) Treatment2A Treatment 2B Treatment 2C 0 0.000 0.000 0.0000 0.25 1.263 0.5 0.396.0553 1.556 0.75 1.972 1 0.800 1.063 1.796 1.25 1.795 1.5 1.038 1.3191.637 1.75 1.467 2 1.269 1.414 1.454 2.5 1.331 3 1.328 1.540 1.320 41.132 1.378 1.011 5 1.291 1.609 0.731 6 1.033 1.242 0.518 7 0.941 0.9550.442 8 0.936 0.817 0.372 10 0.669 0.555 0.323 12 0.766 0.592 0.398 140.641 0.519 0.284 16 0.547 0.407 0.223 18 0.453 0.320 0.173 20 0.3820.280 24 0.315 0.254 28 0.352 0.319 32 0.304 0.237 36 0.252 0.207 480.104 0.077

The results are shown graphically in FIG. 6. Again, the results havebeen normalized to a 20 mg dosage. As with Study 1, the immediaterelease liquid of Treatment 2C shows a classical curve, with a high andrelatively narrow peak, followed by an exponential drop in plasmaconcentration, while the controlled release oxymorphone tablets exhibittriple peaks in blood plasma concentration. Thus, again when we refer tothe time to peak plasma concentration (T_(max)) unless otherwisespecified, we refer to the time to the second peak.

TABLE 10 Pharmacokinetic Parameters of Plasma Oxymorphone for Study 2Treatment 2A Treatment 2B Treatment 2C Mean SD Mean SD Mean SD C_(max)1.644 0.365 1.944 0.465 4.134 0.897 T_(max) 3.07 1.58 2.93 1.64 0.9470.313 AUC_((0-t)) 22.89 5.486 21.34 5.528 21.93 5.044 AUC_((0-inf))25.28 5.736 23.62 5.202 24.73 6.616 T_(1/2el) 12.8 3.87 11.0 3.51 5.012.02 Units: C_(max) in ng/ml, T_(max) in hours, AUC in ng * hr/ml,T_(1/2el) in hours.

In Table 10, the T_(max) has a large standard deviation due to the twocomparable peaks in blood plasma concentration. Relative bioavailabilitydeterminations are set forth in Tables 11 and 12.

TABLE 11 Relative Bioavailability Determination Based on AUC_((0–inf))F_(rel) (2A vs. 2C) F_(rel) (2B vs. 2C) F_(rel) (2A vs. 2B) 1.052 .±.0.187 0.949 .±. 0.154 1.148 .±. 0.250

TABLE 12 Relative bioavailability Determination Based on AUC_((0–18))F_(rel) (2A vs. 2C) F_(rel) (2B vs. 2C) F_(rel) (2A vs. 2B) 0.690 .±.0.105 0.694 .±. 0.124 1.012 .±. 0.175

As may be seen from tables 5 and 10 and FIGS. 1 and 2, the C_(max) forthe CR tablets (treatments 1A, 1B, 2A and 2B) is considerably lower, andthe T_(max) much higher than for the immediate release oxymorphone. Theblood plasma level of oxymorphone remains high well past the 8 (or eventhe 12) hour dosing interval desired for an effective controlled releasetablet.

Study 3-One Controlled Release Formulation; Fed and Fasted Patients

This study had a single-center, open-label, analytically blinded,randomized, four-way crossover design. Subjects randomized to Treatment3A and Treatment 3C, as described below, were in a fasted statefollowing a 10-hour overnight fast. Subjects randomized to Treatment 3Band Treatment 3D, as described below, were in the fed state, having hada high fat meal, completed ten minutes prior to dosing. There was a14-day washout interval between the four dose administrations. Thesubjects were confined to the clinic during each study period. Subjectsassigned to receive Treatment 3A and Treatment 3B were discharged fromthe clinic on Day 3 following the 48-hour procedures, and subjectsassigned to receive Treatment 3C and Treatment 3D were discharged fromthe clinic on Day 2 following the 36-hour procedures. On Day 1 of eachstudy period the subjects received one of four treatments:

Treatments 3A and 3B: Oxymorphone controlled release 20 mg tablets fromExample 3. Subjects randomized to Treatment 3A received a single oraldose of one 20 mg oxymorphone controlled release tablet taken with 240ml of water after a 10-hour fasting period. Subjects randomized toTreatment 3B received a single oral dose of one 20 mg oxymorphonecontrolled release tablet taken with 240 ml of water 10 minutes after astandardized high fat meal.

Treatments 3C and 3D: oxymorphone HCl solution, USP, 1.5 mg/ml 10 mlvials. Subjects randomized to Treatment 3C received a single oral doseof 10 mg (6.7 ml) oxymorphone solution taken with 240 ml of water aftera 10-hour fasting period. Subjects randomized to Treatment 3D received asingle oral dose of 10 mg (6.7 ml) oxymorphone solution taken with 240ml of water 10 minutes after a standardized high-fat meal.

A total of 28 male subjects were enrolled in the study, and 24 subjectscompleted the study. The mean age of the subjects was 27 years (range of19 through 38 years), the mean height of the subjects was 69.6 inches(range of 64.0 through 75.0 inches), and the mean weight of the subjectswas 169.0 pounds (range 117.0 through 202.0 pounds).

A total of 28 subjects received at least one treatment. Only subjectswho completed all 4 treatments were included in the summary statisticsand statistical analysis.

Blood samples (7 ml) were collected during each study period at the 0hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16,20, 24, 30, 36, and 48 hours post-dose (19 samples) for subjectsrandomized to Treatment 3A and Treatment 3B. Blood samples (7 ml) werecollected during each study period at the 0 hour (predose), and at 0.25,0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, and36 hours post-dose (21 samples) for subjects randomized to Treatment 3Cand Treatment 3D.

The mean oxymorphone plasma concentration versus time curves forTreatments 3A, 3B, 3C, and 3D are presented in FIG. 7. The results havebeen normalized to a 20 mg dosage. The data is contained in Table 13.The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistics for all Treatments are summarized in Table14.

TABLE 13 Mean Plasma Concentration vs. Time (ng/ml) Treatment TreatmentTreatment Treatment Time (hr) 3A 3B 3C 3D 0 0.0084 0.0309 0.0558 0.00000.25 0.5074 0.9905 0.5 0.3853 0.3380 0.9634 1.0392 0.75 0.9753 1.3089 10.7710 0.7428 0.8777 1.3150 1.25 0.8171 1.2274 1.5 0.7931 1.0558 0.71091.1638 1.75 0.6357 1.0428 2 0.7370 1.0591 0.5851 0.9424 3 0.6879 0.98580.4991 0.7924 4 0.6491 0.9171 0.3830 0.7277 5 0.9312 1.4633 0.31110.6512 6 0.7613 1.0441 0.2650 0.4625 8 0.5259 0.7228 0.2038 0.2895 100.4161 0.5934 0.1768 0.2470 12 0.5212 0.5320 0.2275 0.2660 14 0.45270.4562 0.2081 0.2093 16 0.3924 0.3712 0.1747 0.1623 20 0.2736 0.30210.1246 0.1144 24 0.2966 0.2636 0.1022 0.1065 30 0.3460 0.3231 36 0.27280.2456 0.0841 0.0743 48 0.1263 0.1241

TABLE 14 Pharmacokinetic Parameters of Plasma Oxymorphone for Study 3Treatment 3B Treatment 3A Treatment 3C Treatment 3D Mean SD Mean SD MeanSD Mean SD C_(max) 1.7895 0.6531 1.1410 0.4537 2.2635 1.0008 3.27331.3169 T_(max) 5.65 9.39 5.57 7.14 0.978 1.14 1.11 0.768 AUC₍₀₋₂₄₎ 14.274.976 11.64 3.869 12.39 4.116 17.30 5.259 AUC_((0-t)) 19.89 6.408 17.718.471 14.53 4.909 19.20 6.030 AUC_((0-inf)) 21.29 6.559 19.29 5.02818.70 6.618 25.86 10.03 T_(1/2el) 12.0 3.64 12.3 3.99 16.2 11.4 20.619.3

The relative bioavailability calculations are summarized in tables 15and 16.

TABLE 15 Relative Bioavailability Determination Based on AUC_((0–inf))F_(rel) (3A vs. 3C) F_(rel) (3B vs. 3D) F_(rel) (3D vs. 3C) F_(rel) (3Avs. 3B) 1.040 .±. 0.8863 .±. 0.2569 1.368 .±. 0.4328 1.169 .±. 0.20410.1874

TABLE 16 Relative bioavailability Determination Based on AUC_((0–24))F_(rel) (3A vs. 2C) F_(rel) (3B vs. 3D) F_(rel) (3D vs. 3C) F_(rel) (3Avs. 3B) 0.9598 .±. 0.8344 .±. 0.100 1.470 .±. 0.3922 1.299 .±. 0.46380.2151

The objectives of this study were to assess the relative bioavailabilityof oxymorphone from oxymorphone controlled release (20 mg) compared tooxymorphone oral solution (10 mg) under both fasted and fed conditions,and to determine the effect of food on the bioavailability ofoxymorphone from the controlled release formulation, oxymorphone CR, andfrom the oral solution.

The presence of a high fat meal had a substantial effect on theoxymorphone C_(max), but less of an effect on oxymorphone AUC fromoxymorphone controlled release tablets. Least Squares (LS) mean C_(max)was 58% higher and LS mean AUC_((0-t)) and AUC_((0-inf)) were 18% higherfor the fed condition (Treatment B) compared to the fasted condition(Treatment A) based on LN-transformed data. This was consistent with therelative bioavailability determination from AUC_((0-inf)) since meanF_(rel) was 1.17. Mean T_(max) values were similar (approximately 5.6hours), and no significant difference in T_(max) was shown usingnonparametric analysis. Half value durations were significantlydifferent between the two treatments.

The effect of food on oxymorphone bioavailability from the oral solutionwas more pronounced, particularly in terms of AUC. LS mean C_(max) was50% higher and LS mean AUC_((0-t)) and AUC_((0-inf)) were 32-34% higherfor the fed condition (Treatment D) compared to the fasted condition(Treatment C) based on LN-transformed data. This was consistent with therelative bioavailability determination from AUC_((0-inf)) since meanF_(rel) was 1.37. Mean T_(max) (approximately 1 hour) was similar forthe two treatments and no significant difference was shown.

Under fasted conditions, oxymorphone controlled release 20 mg tabletsexhibited similar extent of oxymorphone availability compared to 10 mgoxymorphone oral solution normalized to a 20 mg dose (Treatment A versusTreatment C). From LN-transformed data, LS mean AUC_((0-t)) was 17%higher for oxymorphone CR, whereas LS mean AUC_((0-inf)) values werenearly equal (mean ratio=99%). Mean F_(rel) values calculated fromAUC_((0-inf)) and AUC₍₀₋₂₄₎, (1.0 and 0.96, respectively) also showedsimilar extent of oxymorphone availability between the two treatments.

As expected, there were differences in parameters reflecting rate ofabsorption. LS mean C_(max) was 49% lower for oxymorphone controlledrelease tablets compared to the dose-normalized oral solution, based onLN-transformed data. Half-value duration was significantly longer forthe controlled release formulation (means, 12 hours versus 2.5 hours).

Under fed conditions, oxymorphone availability from oxymorphonecontrolled release 20 mg was similar compared to 10 mg oxymorphone oralsolution normalized to a 20 mg dose (Treatment B versus Treatment D).From LN-transformed data, LS mean AUC_((0-inf)) was 12% lower foroxymorphone CR. Mean F_(rel) values calculated from AUC_((0-inf)) andAUC₍₀₋₂₄₎, (0.89 and 0.83 respectively) also showed similar extent ofoxymorphone availability from the tablet. As expected, there weredifferences in parameters reflecting rate of absorption. LS mean C_(max)was 46% lower for oxymorphone controlled release tablets compared to thedose-normalized oral solution, based on LN-transformed data. MeanT_(max) was 5.7 hours for the tablet compared to 1.1 hours for the oralsolution. Half-value duration was significantly longer for thecontrolled release formulation (means, 7.8 hours versus 3.1 hours).

The presence of a high fat meal did not appear to substantially affectthe availability of 6-hydroxymorphone following administration ofoxymorphone controlled release tablets. LS mean ratios were 97% forAUC_((0-t)) and 91% for C_(max) (Treatment B versus A), based onLN-transformed data. This was consistent with the relativebioavailability determination from AUC₍₀₋₂₄₎, since mean F_(rel) was0.97. Mean T_(max), was later for the fed treatment compared to thefasted treatment (5.2 and 3.6 hours, respectively), and difference wassignificant.

Under fasted conditions, oxymorphone controlled release 20 mg tabletsexhibited similar availability of 6-hydroxymorphone compared to 10 mgoxymorphone oral solution normalized to a 20 mg dose (Treatment A versusTreatment C). From LN-transformed data, LS mean ratio for AUC_((0-t))was 104.5%. Mean F_(rel) (0.83) calculated from AUC₍₀₋₂₄₎ also showedsimilar extent of oxymorphone availability between the two treatments.Mean T_(max) was 3.6 hours for the tablet compared to 0.88 for the oralsolution. Half-value duration was significantly longer for thecontrolled release formulation (means, 11 hours versus 2.2 hours).

Under fed conditions, availability of 6-hydroxymorphone from oxymorphonecontrolled release 20 mg was similar compared to 10 mg oxymorphone oralsolution normalized to a 20 mg dose (Treatment B versus Treatment D).From LN-transformed data, LS mean AUC_((0-t)) was 14% higher foroxymorphone CR. Mean F_(rel) (0.87) calculated from AUC₍₀₋₂₄₎ alsoindicated similar extent of availability between the treatments. MeanT_(max) was 5.2 hours for the tablet compared to 1.3 hour for the oralsolution. Half-value duration was significantly longer for thecontrolled release formulation (means, 14 hours versus 3.9 hours).

The extent of oxymorphone availability from oxymorphone controlledrelease 20 mg tablets was similar under fed and fasted conditions sincethere was less than a 20% difference in LS mean AUC_((0-t)) andAUC_((0-inf)) values for each treatment, based on LN-transformed data.T_(max) was unaffected by food; however, LS mean C_(max) was increased58% in the presence of the high fat meal. Both rate and extent ofoxymorphone absorption from the oxymorphone oral solution were affectedby food since LS mean C_(max) and AUC values were increasedapproximately 50 and 30%, respectively. T_(max) was unaffected by food.Under both fed and fasted conditions, oxymorphone controlled releasetablets exhibited similar extent of oxymorphone availability compared tooxymorphone oral solution since there was less than a 20% difference inLS mean AUC(0-t) and AUC(0-inf) values for each treatment.

Bioavailability of 6-hydroxymorphone following oxymorphone controlledrelease 20 mg tablets was also similar under fed and fasted conditionssince there was less than a 20% difference in LS mean C_(max) and AUCvalues for each treatment. T_(max) was later for the fed condition. Thepresence of food did not affect the extent of availability fromoxymorphone oral solution since LS mean AUC values were less than 20%different. However, C_(max) was decreased 35% in the presence of food.T_(max) was unaffected by food. Under both fed and fasted conditions,oxymorphone controlled release tablets exhibited similar extent ofavailability compared to oxymorphone oral solution since there was lessthan a 20% difference in LS mean AUC values for each treatment.

The mean 6-OH oxymorphone plasma concentration versus time curves forTreatments 3A, 3B, 3C, and 3D are presented in FIG. 8. The data iscontained in Table 17.

TABLE 17 Mean Plasma Concentration vs. Time (ng/ml) 6-HydroxyoxymorphoneTreatment Treatment Treatment Treatment Time (hr) 3A 3B 3C 3D 0 0.00690.0125 0.0741 0.0000 0.25 0.7258 0.4918 0.5 0.5080 0.1879 1.2933 0.59720.75 1.3217 0.7877 1 1.0233 0.4830 1.1072 0.8080 1.25 1.0069 0.7266 1.51.1062 0.7456 0.8494 0.7001 1.75 0.7511 0.6472 2 1.0351 0.7898 0.65540.5758 3 0.9143 0.7619 0.6196 0.5319 4 0.8522 0.7607 0.4822 0.5013 50.8848 0.8548 0.3875 0.4448 6 0.7101 0.7006 0.3160 0.3451 8 0.54210.5681 0.2525 0.2616 10 0.4770 0.5262 0.2361 0.2600 12 0.4509 0.44540.2329 0.2431 14 0.4190 0.4399 0.2411 0.2113 16 0.4321 0.4230 0.23850.2086 20 0.3956 0.4240 0.2234 0.1984 24 0.4526 0.4482 0.2210 0.2135 300.4499 0.4708 36 0.3587 0.3697 0.1834 0.1672 48 0.3023 0.3279

TABLE 18 Pharmacokinetic Parameters of Plasma Oxymorphone for Study 3Treatment 3A Treatment 3B Treatment 3C Treatment 3D Mean SD Mean SD MeanSD Mean SD C_(max) 1.2687 0.5792 1.1559 0.4848 1.5139 0.7616 0.97480.5160 T_(max) 3.61 7.17 5.20 9.52 0.880 0.738 1.30 1.04 AUC_((0-t))22.47 10.16 22.01 10.77 10.52 4.117 9.550 4.281 AUC_((0-inf)) 38.3923.02 42.37 31.57 20.50 7.988 23.84 11.37 T_(1/2el) 39.1 36.9 39.8 32.629.3 12.0 44.0 35.00

Study 4-Controlled Release 20 mg vs Immediate Release 10 mg

A study was conducted to compare the bioavailability andpharmacokinetics of controlled release and immediate release oxymorphonetablets under single-dose and multiple-dose (steady state) conditions.For the controlled release study, healthy volunteers received a singledose of a 20 mg controlled release oxymorphone table on the morning ofDay 1. Beginning on the morning of Day 3, the volunteers wereadministered a 20 mg controlled release oxymorphone tablet every 12hours through the morning dose of Day 9. For the immediate releasestudy, healthy volunteers received a single 10 mg dose of an immediaterelease oxymorphone tablet on the morning of Day 1. On the morning ofDay 3, additional 10 mg immediate release tablets were administeredevery six hours through the first two doses on Day 9.

FIG. 9 shows the average plasma concentrations of oxymorphone and6-hydroxyoxymorphone for all subjects after a single dose eithercontrolled release (CR) 20 mg or immediate release (IR) 10 mgoxymorphone. The data in the figure (as with the other relativeexperimental data herein) is normalized to a 20 mg dose. The immediaterelease tablet shows a classical curve, with a high, relatively narrowpeak followed by an exponential drop in plasma concentration. Thecontrolled release oxymorphone tablets show a lower peak with extendedmoderate levels of oxymorphone and 6-hydroxy oxymorphone. Table 19 showsthe levels of oxymorphone and 6-hydroxy oxymorphone from FIG. 9 intabular form.

TABLE 19 Mean Plasma Concentration (ng/ml) Oxymorphone6-Hydroxyoxymorphone Controlled Immediate Controlled Immediate ReleaseRelease Release Release Hour 20 mg 10 mg 20 mg 10 mg 0.00 0.00 0.00 0.000.00 0.25 0.22 1.08 0.14 0.73 0.50 0.59 1.69 0.45 1.22 1.00 0.77 1.190.53 0.79 1.50 0.84 0.91 0.53 0.57 2.00 0.87 0.75 0.60 0.47 3.00 0.830.52 0.55 0.34 4.00 0.73 0.37 0.53 0.27 5.00 0.94 0.36 0.46 0.23 6.000.81 0.28 0.41 0.18 8.00 0.73 0.20 0.37 0.14 10.0 0.60 0.19 0.35 0.1512.0 0.67 0.25 0.32 0.13 16.0 0.39 0.16 0.29 0.13 24.0 0.23 0.07 0.290.13 30.0 0.12 0.01 0.17 0.04 36.0 0.05 0.00 0.11 0.00 48.0 0.00 0.000.07 0.01

FIG. 10 shows the average plasma concentrations of oxymorphone and6-hydroxyoxymorphone for all subjects in the steady state test, fordoses of controlled release 20 mg tablets and immediate release 10 mgtablets of oxymorphone. The figure shows the plasma concentrations afterthe final controlled release tablet is given on Day 9, and the finalimmediate release tablet is given 12 hours thereafter. The steady stateadministration of the controlled release tablets clearly shows a steadymoderate level of oxymorphone ranging from just over 1 ng/ml to almost1.75 ng/ml over the course of a twelve hour period, where the immediaterelease tablet shows wide variations in blood plasma concentration.Table 20 shows the levels of oxymorphone and 6-hydroxyoxymorphone fromFIG. 10 in tabular form.

TABLE 20 Summary of Mean Plasma Concentration (ng/ml) Oxymorphone6-Hydroxyoxymorphone Controlled Immediate Controlled Immediate ReleaseRelease Release Release Day Hour 20 mg 10 mg 20 mg 10 mg 4 0.00 1.100.75 0.89 0.72 5 0.00 1.12 0.84 1.15 0.88 6 0.00 1.20 0.92 1.15 0.87 70.00 1.19 0.91 1.27 1.00 8 0.00 1.19 0.86 1.29 0.98 9 0.00 1.03 1.071.09 1.05 0.25 2.64 1.70 0.50 3.12 1.50 2.09 1.00 2.47 1.70 1.68 1.502.05 1.63 1.55 2.00 1.78 1.64 1.30 3.00 1.27 1.47 1.11 4.00 0.98 1.390.98 5.00 1.01 1.21 0.89 6.00 0.90 1.06 0.84 6.25 1.17 0.88 6.50 1.881.06 7.00 2.12 1.20 7.50 2.24 1.15 8.00 1.32 2.01 0.97 1.03 9.00 1.520.90 10.0 1.32 1.24 0.85 0.84 11.0 1.11 0.74 12.0 1.18 0.96 0.79 0.70

TABLE 21 Mean Single-Dose Pharmacokinetic Results Controlled ImmediateRelease 20 mg Release 10 mg 6-OH- 6-OH- oxymorphone oxymorphoneoxymorphone oxymorphone AUC_((o–t)) 14.74 11.54 7.10 5.66 AUC_((o–inf))15.33 16.40 7.73 8.45 C_(max)(ng/ml) 1.12 0.68 1.98 1.40 T_(max)(hr)5.00 2.00 0.50 0.50 T½(hr) 9.25 26.09 10.29 29.48

Parent 6-OH oxymorphone AUC_((0-t)) values were lower than the parentcompound after administration of either dosage form, but theAUC_((0-inf)) values are slightly higher due to the longer half-life forthe metabolite. This relationship was similar for both theimmediate-release (IR) and controlled release (CR) dosage forms. Asrepresented by the average plasma concentration graph, the CR dosageform has a significantly longer time to peak oxymorphone concentrationand a lower peak oxymorphone concentration. The 6-OH oxymorphone peakoccurred sooner than the parent peak following the CR dosage form, andsimultaneously with the parent peak following the IR dosage form.

It is important to note that while the present invention is describedand exemplified using 20 mg tablets, the invention may also be used withother strengths of tablets. In each strength, it is important to notehow a 20 mg tablet of the same composition (except for the change instrength) would act. The blood plasma levels and pain intensityinformation are provided for 20 mg tablets, however the presentinvention is also intended to encompass 5 to 80 mg controlled releasetablets. For this reason, the blood plasma level of oxymorphone or6-hydroxyoxymorphone in nanograms per milliliter of blood, per mgoxymorphone (ng/mg·ml) administered is measured. Thus at 0.02 ng/mg·ml,a 5 mg tablet should produce a minimum blood plasma concentration of 0.1ng/ml. A stronger tablet will produce a higher blood plasmaconcentration of active molecule, generally proportionally. Uponadministration of a higher dose tablet, for example 80 mg, the bloodplasma level of oxymorphone and 6-OH oxymorphone may more than quadruplecompared to a 20 mg dose, although conventional treatment of lowbioavailability substances would lead away from this conclusion. If thisis the case, it may be because the body can only process a limitedamount oxymorphone at one time. Once the bolus is processed, the bloodlevel of oxymorphone returns to a proportional level.

It is the knowledge that controlled release oxymorphone tablets arepossible to produce and effective to use, which is most important, madepossible with the high bioavailability of oxymorphone in a controlledrelease tablet. This also holds true for continuous periodicadministration of controlled release formulations. The intent of acontrolled release opioid formulation is the long-term management ofpain. Therefore, the performance of a composition when administeredperiodically (one to three times per day) over several days isimportant. In such a regime, the patient reaches a “steady state” wherecontinued administration will produce the same results, when measured byduration of pain relief and blood plasma levels of pharmaceutical. Sucha test is referred to as a “steady state” test and may require periodicadministration over an extended time period ranging from several days toa week or more. Of course, since a patient reaches steady state in sucha test, continuing the test for a longer time period should not affectthe results. Further, when testing blood plasma levels in such a test,if the time period for testing exceeds the interval between doses, it isimportant the regimen be stopped after the test is begun so thatobservations of change in blood level and pain relief may be madewithout a further dose affecting these parameters.

Study 5-Controlled Release 40 mg vs Immediate Release 4.Times.10 mgunder Fed and Fasting Conditions

The objectives of this study were to assess the relative bioavailabilityof oxymorphone from oxymorphone controlled release (40 mg) compared tooxymorphone immediate release (4.times.10 mg) under both fasted and fedconditions, and to determine the effect of food on the bioavailabilityof oxymorphone from the controlled release formulation, oxymorphone CR,and from the immediate release formulation, oxymorphone IR.

This study had a single-center, open-label, analytically blinded,randomized, four-way crossover design. Subjects randomized to Treatment5A and Treatment 5C, as described below, were in a fasted statefollowing a 10-hour overnight fast. Subjects randomized to Treatment 5Band Treatment 5D, as described below, were in the fed state, having hada high fat meal, completed ten minutes prior to dosing. There was a14-day washout interval between the four dose administrations. Thesubjects were confined to the clinic during each study period. Subjectassigned to receive Treatment 5A and Treatment 5B were discharged fromthe clinic on Day 3 following the 48-hour procedures, and subjectsassigned to receive Treatment 5C and Treatment 5D were discharged fromthe clinic on Day 2 following the 36-hour procedures. On Day 1 of eachstudy period the subjects received one of four treatments:

Treatments 5A and 5B: Oxymorphone controlled release 40 mg tablets fromTable 2. Subjects randomized to Treatment 5A received a single oral doseof one 40 mg oxymorphone controlled release tablet taken with 240 ml ofwater after a 10-hour fasting period. Subjects randomized to Treatment5B received a single oral dose of one 40 mg oxymorphone controlledrelease tablet taken with 240 ml of water 10 minutes after astandardized high fat meal.

Treatments 5C and 5D: Immediate release tablet (IR) 4.times.10 mgOxymorphone. Subjects randomized to Treatment 5C received a single oraldose of 4.times.10 mg oxymorphone IR tablet taken with 240 ml of waterafter a 10-hour fasting period. Subjects randomized to Treatment 5Dreceived a single oral dose of 4.times.10 mg oxymorphone IR tablet takenwith 240 ml of water 10 minutes after a standardized high-fat meal.

A total of 28 male subjects were enrolled in the study, and 25 subjectscompleted the study. A total of 28 subjects received at least onetreatment. Only subjects who completed all 4 treatments were included inthe summary statistics and statistical analysis.

Blood samples (7 ml) were collected during each study period at the 0hour (predose), and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10,12, 24, 36, 48, 60, and 72 hours post-dose (19 samples) for subjectsrandomized to all Treatments.

The mean oxymorphone plasma concentration versus time is presented inTable 22. The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistics for all Treatments are summarized in Table23.

TABLE 22 Mean Plasma Concentration vs. Time (ng/ml) Treatment TreatmentTreatment Treatment Time (hr) 5A 5B 5C 5D 0 0.00 0.00 0.00 0.00 0.250.47 0.22 3.34 1.79 0.50 1.68 0.97 7.28 6.59 0.75 1.92 1.90 6.60 9.49 12.09 2.61 6.03 9.91 1.5 2.18 3.48 4.67 8.76 2 2.18 3.65 3.68 7.29 3 2.002.86 2.34 4.93 4 1.78 2.45 1.65 3.11 5 1.86 2.37 1.48 2.19 6 1.67 2.021.28 1.71 8 1.25 1.46 0.92 1.28 10 1.11 1.17 0.78 1.09 12 1.34 1.21 1.041.24 24 0.55 0.47 0.40 0.44 36 0.21 0.20 0.16 0.18 48 0.06 0.05 0.040.05 60 0.03 0.01 0.01 0.01 72 0.00 0.00 0.00 0.00

TABLE 23 Pharmacokinetic Parameters of Plasma Oxymorphone for Study 5Treatment Treatment Treatment Treatment 5A 5B 5C 5D Mean SD Mean SD MeanSD Mean SD C_(max) 2.79 0.84 4.25 1.21 9.07 4.09 12.09 5.42 T_(max) 2.262.52 1.96 1.06 0.69 0.43 1.19 0.62 AUC_((0-t)) 35.70 10.58 38.20 11.0436.00 12.52 51.35 20.20 AUC_((0-inf)) 40.62 11.38 41.17 10.46 39.0412.44 54.10 20.26 T_(1/2el) 12.17 7.57 10.46 5.45 11.65 6.18 9.58 3.63

The relative bioavailability calculations are summarized in Tables 24and 25.

TABLE 24 Relative Bioavailability Determination Based on AUC_((o–inf))F_(rel) (5D vs. 5C) F_(rel) (5B vs. 5A) 1.3775 1.0220

TABLE 25 Relative bioavailability Determination Based on AUC_((o–24))F_(rel) (5D vs. 5C) F_(rel) (5B vs. 5A) 1.4681 1.0989

The mean 6-OH oxymorphone plasma concentration versus time is presentedin Table 26.

TABLE 26 Mean Plasma Concentration vs. Time (ng/ml) 6-HydroxyoxymorphoneTreatment Treatment Treatment Treatment Time (hr) 5A 5B 5C 5D 0 0.000.00 0.00 0.00 0.25 0.27 0.05 2.36 0.50 0.50 1.32 0.31 5.35 1.98 0.751.37 0.59 4.53 2.97 1 1.44 0.82 3.81 2.87 1.5 1.46 1.09 2.93 2.58 2 1.461.28 2.37 2.29 3 1.39 1.14 1.69 1.72 4 1.25 1.14 1.33 1.26 5 1.02 1.001.14 1.01 6 0.93 0.86 0.94 0.86 8 0.69 0.72 0.73 0.77 10 0.68 0.67 0.660.75 12 0.74 0.66 0.70 0.77 24 0.55 0.52 0.54 0.61 36 0.23 0.30 0.280.27 48 0.18 0.20 0.20 0.19 60 0.09 0.10 0.09 0.09 72 0.06 0.06 0.040.05

TABLE 27 Pharmacokinetic Parameters of Plasma 6-Hydroxyoxymorphone forStudy 5 Treatment Treatment Treatment Treatment 5A 5B 5C 5D Mean SD MeanSD Mean SD Mean SD C_(max) 1.88 0.69 1.59 0.63 6.41 3.61 3.79 1.49T_(max) 1.48 1.18 2.73 1.27 0.73 0.47 1.18 0.74 AUC_((0-t)) 28.22 10.8126.95 11.39 33.75 10.29 32.63 13.32 AUC_((0-inf)) 33.15 11.25 32.9810.68 37.63 17.01 36.54 13.79 T_(1/2el) 17.08 7.45 21.92 8.41 16.01 6.6816.21 7.42

The above description incorporates preferred embodiments and examples asa means of describing and enabling the invention to be practiced by oneof skill in the art. It is imagined that changes can be made withoutdeparting from the spirit and scope of the invention described hereinand defined in the appended claims.

1. An oral controlled release oxymorphone formulation, comprising: a.about 5 mg to about 80 mg of oxymorphone or a pharmaceuticallyacceptable salt of oxymorphone; and b. a hydrophilic material, whereinupon oral administration of the formulation to a subject in need of ananalgesic effect: (i) the formulation provides detectable blood plasmalevels of 6-OH oxymorphone and oxymorphone; (ii) the blood plasma levelsof 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8hours after administration; (iii) the blood plasma levels of 6-OHoxymorphone and oxymorphone exhibit a ratio of area under the curve(AUC_((0 to inf))) of blood plasma level versus time for 6-OHoxymorphone compared to oxymorphone in a range of about 0.5 to about1.5; (iv) the duration of the analgesic effect is through at least about12 hours after administration; and (v) the blood plasma levels ofoxymorphone exhibit two or three peaks within about 12 hours afteradministration.
 2. The formulation of claim 1 wherein the hydrophilicmaterial is selected from the group consisting of a gum, a celluloseether, an acrylic resin, a protein-derived material, and mixturesthereof.
 3. The formulation of claim 1 wherein the hydrophilic materialis a gum selected from the group consisting of a heteropolysaccharidegum, a homopolysaccharide gum, and mixtures thereof.
 4. The formulationof claim 3 wherein the gum is selected from the group consisting ofxanthan, tragacanth, acacia, karaya, alginates, agar, guar,hydroxypropyl guar, carrageenan, locust bean, and mixtures thereof. 5.The formulation of claim 1 wherein the hydrophilic material is acellulose ether selected from the group consisting of a hydroxyalkylcellulose, a carboxyalkyl cellulose, and mixtures thereof.
 6. Theformulation of claim 1 wherein the hydrophilic material is selected fromthe group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, carboxymethylcellulose, and mixturesthereof.
 7. The formulation of claim 1 wherein the hydrophilic materialcomprises at least one of: i. a heteropolysaccharide; or ii. aheteropolysaccharide and a cross-linking agent capable of cross-linkingthe heteropolysaccharide; or iii. a mixture of (i), (ii) and apolysaccharide gum.
 8. The formulation of claim 7 wherein theheteropolysaccharide is a water soluble polysaccharide containing two ormore kinds of sugar units and having a branched or helicalconfiguration.
 9. The formulation of claim 7 wherein theheteropolysaccharide is selected from the group consisting of xanthangum, deacylated xanthan gum, carboxymethyl ether xanthan gum, propyleneglycol ester xanthan gum and mixtures thereof.
 10. The formulation ofclaim 7 wherein the cross-linking agent is a homopolysaccharide gum. 11.The formulation of claim 1 further comprising a hydrophobic polymer. 12.A method of treating pain in a subject in need thereof, the methodcomprising the step of administering to the subject the formulation ofclaim
 1. 13. A pharmaceutical tablet prepared by: a. mixing oxymorphoneor a pharmaceutically acceptable salt of oxymorphone and controlledrelease granules comprising a hydrophilic material and one or moreoptional excipients; and b. directly compressing the mixture of (a) toform the tablet, wherein upon placement of the tablet in an in vitrodissolution test comprising USP Paddle Method at 50 rpm in 500 ml mediahaving a pH of 1.2 to 6.8 at 37° C., about 15% to about 50%, by weight,of the oxymorphone or salt thereof is released from the tablet at about1 hour in the test.
 14. The tablet preparation of claim 13 wherein thehydrophilic material is selected from the group consisting of a gum, acellulose ether, an acrylic resin, a protein-derived material, andmixtures thereof.
 15. The tablet preparation of claim 13 wherein thehydrophilic material is a gum selected from the group consisting of aheteropolysaccharide gum, a homopolysaccharide gum, and mixturesthereof.
 16. The tablet preparation of claim 13 wherein the hydrophilicmaterial is a cellulose ether selected from the group consisting of ahydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures thereof.17. The tablet preparation of claim 13 wherein the hydrophilic materialis hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and mixtures thereof.
 18. Thetablet preparation of claim 13 wherein the hydrophilic materialcomprises at least one of: i. a heteropolysaccharide; or ii. aheteropolysaccharide and a cross-linking agent capable of cross-linkingthe heteropolysaccharide; or iii. a mixture of (i), (ii) and apolysaccharide gum.
 19. The tablet preparation of claim 18 wherein theheteropolysaccharide is a water soluble polysaccharide containing two ormore kinds of sugar units and having a branched or helicalconfiguration.
 20. The tablet preparation of claim 19 wherein theheteropolysaccharide is selected from the group consisting of xanthangum, deacylated xanthan gum, carboxymethyl ether xanthan gum, propyleneglycol ester xanthan gum and mixtures thereof.
 21. A pharmaceuticaltablet prepared by: a. mixing oxymorphone or a pharmaceuticallyacceptable salt of oxymorphone and one or more controlled releaseexcipients; and b. forming the tablet, wherein upon placement of thetablet in an in vitro dissolution test comprising USP Paddle Method at50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37° C., about 15% toabout 50%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 1 hour in the test; and wherein upon oraladministration to a human subject the tablet alleviates pain for 12 to24 hours.
 22. The tablet of claim 21 wherein about 45% to about 80%, byweight, of the oxymorphone or salt thereof is released from the tabletat about 4 hours in the test, and at least about 80%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 10hours in the test.
 23. The tablet of claim 21 wherein at least 27%, byweight, of the oxymorphone or salt thereof is released from the tabletat about 1 hour in the test, at least 40%, by weight, of the oxymorphoneor salt thereof is released from the tablet at about 2 hours in thetest, at least 50%, by weight, of the oxymorphone or salt thereof isreleased from the tablet at about 3 hours in the test, at least 64%, byweight, of the oxymorphone or salt thereof is released from the tabletat about 5 hours in the test, at least 70%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 6 hoursin the test, at least 79%, by weight, of the oxymorphone or salt thereofis released from the tablet at about 8 hours in the test, at least 85%,by weight, of the oxymorphone or salt thereof is released from thetablet at about 10 hours in the test, and at least 89%, by weight, ofthe oxymorphone or salt thereof is released from the tablet at about 12hours in the test.
 24. The tablet of claim 21, wherein at least 27%, byweight, of the oxymorphone or salt thereof is released from the tabletat about 1 hour in the test.
 25. The tablet of claim 21, wherein atleast 40%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 2 hours in the test.
 26. The tablet of claim21, wherein at least 50%, by weight, of the oxymorphone or salt thereofis released from the tablet at about 3 hours in the test.
 27. The tabletof claim 21, wherein at least 64%, by weight, of the oxymorphone or saltthereof is released from the tablet at about 5 hours in the test. 28.The tablet of claim 21, wherein at least 70%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 6 hoursin the test.
 29. The tablet of claim 21, wherein at least 79%, byweight, of the oxymorphone or salt thereof is released from the tabletat about 8 hours in the test.
 30. The tablet of claim 21, wherein atleast 85%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 10 hours in the test.
 31. A method for treatingpain in a human subject in need of acute or chronic pain relief,comprising the steps of: (a) Providing a solid oral dosage form of acontrolled release oxymorphone formulation with a release rate profiledesigned to provide adequate blood plasma levels over at least 12 hoursto provide sustained pain relief over this same period comprising about5 mg to about 80 mg oxymorphone or a pharmaceutically acceptable saltthereof wherein oxymorphone is the sole active ingredient, and whereinupon placement of the composition in an in vitro dissolution testcomprising USP Paddle Method at 50 rpm in 500 ml media having a pH of1.2 to 6.8 at 37° C., about 15% to about 50%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 1 hourin the test; and (b) administering a single dose of the dosage form tothe subject, wherein the oxymorphone C_(max) is at least 50% higher whenthe dosage form is administered to the subject under fed as compared tofasted conditions.
 32. The method of claim 31 wherein the dosage formcomprises about 40 mg oxymorphone or a pharmaceutically acceptable saltthereof, and wherein the oxymorphone C_(max) is about 58% higher whenthe dosage form is administered to the subject under fed as compared tofasted conditions.
 33. The method of claim 31 wherein the dosage formcomprises about 20 mg oxymorphone or a pharmaceutically acceptable saltthereof.
 34. The method of claim 31 wherein the dosage form comprisesabout 20 mg to about 40 mg oxymorphone hydrochloride.
 35. The method ofclaim 31 wherein the difference in the oxymorphone area under the curve(AUC_((0-inf)) between fed and fasted conditions is less than 20%. 36.The method of claim 35 wherein the difference in AUC_((0-inf)) betweenfed and fasted conditions is about 18%.
 37. The method of claim 31wherein upon oral administration of the dosage form to the subject underfed or fasting conditions: (i) the dosage form provides detectable bloodplasma levels of 6-OH oxymorphone and oxymorphone; (ii) the blood plasmalevels of 6-OH oxymorphone and oxymorphone peak within about 1 hour toabout 8 hours after administration; and (iii) the blood plasma levels of6-OH oxymorphone and oxymorphone exhibit a ratio of AUC_((0-inf)) ofblood plasma level versus time for 6-OH oxymorphone compared tooxymorphone in a range of about 0.5 to about 1.5.
 38. A method fortreating pain in a human subject in need of acute or chronic painrelief, comprising the steps of: (a) Providing a solid oral dosage formcomprising about 5 mg to about 80 mg oxymorphone or a pharmaceuticallyacceptable salt thereof in a controlled release delivery system with arelease rate profile designed to provide adequate blood plasma levelsover at least 12 hours to provide sustained pain relief over this sameperiod, wherein oxymorphone is the sole active ingredient, and whereinupon placement of the composition in an in vitro dissolution testcomprising USP Paddle Method at 50 rpm in 500 ml media having a pH of1.2 to 6.8 at 37° C., about 15% to about 50%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 1 hourin the test, about 45% to about 80%, by weight, of the oxymorphone orsalt thereof is released from the tablet at about 4 hours in the test,and at least about 80%, by weight, of the oxymorphone or salt thereof isreleased from the tablet at about 10 hours in the test; and (b)administering a single dose of the dosage form to the subject, whereinthe oxymorphone C_(max) is at least 50% higher when the dosage form isadministered to the subject under fed versus fasted conditions.
 39. Themethod of claim 38 wherein the oxymorphone C_(max) is at least about 58%higher when the dosage form is administered to the subject under fed ascompared to fasted conditions.
 40. The method of claim 38 wherein thedifference in the oxymorphone area under the curve AUC_((0-inf)) betweenfed and fasted conditions is less than 20%.
 41. The method of claim 40wherein the difference in AUC_((0-inf)) between fed and fastedconditions is about 18%.
 42. The method of claim 38 wherein upon oraladministration of the dosage form to the subject under fed or fastingconditions: (i) the dosage form provides detectable blood plasma levelsof 6-OH oxymorphone and oxymorphone; (ii) the blood plasma levels of6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8hours after administration; and (iii) the blood plasma levels of 6-OHoxymorphone and oxymorphone exhibit a ratio of AUC_((0-inf)) of bloodplasma level versus time for 6-OH oxymorphone compared to oxymorphone ina range of about 0.5 to about 1.5.
 43. The method of claim 38 whereinthe system further comprises a hydrophilic material.
 44. The method ofclaim 43 wherein the hydrophilic material is selected from the groupconsisting of a gum, a cellulose ether, an acrylic resin, aprotein-derived material, and mixtures thereof.
 45. The method of claim44 wherein the hydrophilic material is a gum selected from the groupconsisting of xanthan, tragacanth, acacia, karaya, alginates, agar,guar, hydroxypropyl guar, carrageenan, locust bean, and mixturesthereof.
 46. The method of claim 43 wherein the hydrophilic material isa cellulose ether selected from the group consisting of a hydroxyalkylcellulose, a carboxyalkyl cellulose, and mixtures thereof.
 47. Themethod of claim 43 wherein the hydrophilic material is selected from thegroup consisting of hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, carboxymethylcellulose, and mixturesthereof.
 48. The method of claim 43 wherein the hydrophilic materialcomprises at least one of: a. a heteropolysaccharide; or b. aheteropolysaccharide and a cross-linking agent capable of cross-linkingthe heteropolysaccharide; or c. a mixture of (a), (b) and apolysaccharide gum.
 49. An analgesically effective controlled releasepharmaceutical composition for oral delivery, comprising: a. acontrolled release delivery system with a release rate profile designedto provide adequate blood plasma levels over at least 12 hours toprovide sustained pain relief over this same period; and b. about 5 mgto about 80 mg of oxymorphone or a pharmaceutically acceptable salt ofoxymorphone, wherein oxymorphone is the sole active ingredient, whereinupon oral administration of a single dose of the composition to a humansubject, the oxymorphone C_(max) is at least 50% higher when the dose isadministered to the subject under fed as compared to fasted conditions,and wherein upon placement of the composition in an in vitro dissolutiontest comprising USP Paddle Method at 50 rpm in 500 ml media having a pHof 1.2 to 6.8 at 37° C., about 15% to about 50%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 1 hourin the test.
 50. The composition of claim 49 wherein upon oraladministration thereof the oxymorphone AUC_((0-inf)) is no more than 20%higher when the dosage form is administered to the subject under fed ascompared to fasted conditions.
 51. The composition of claim 49 whereinthe dosage form comprises about 40 mg oxymorphone, and wherein theoxymorphone C_(max) is about 58% higher when the dosage form isadministered to the subject under fed as compared to fasted conditions.52. The composition of claim 49 wherein the controlled release deliverysystem comprises a heteropolysaccharide and an agent capable ofcross-linking the heteropolysaccharide in presence of gastrointestinalfluid.
 53. The composition of claim 52 wherein the heteropolysaccharideand the agent capable of cross-linking the heteropolysaccharide arepresent in a weight ratio of about 1:3 to about 3:1.
 54. The compositionof claim 49 wherein about 45% to about 80%, by weight, of theoxymorphone or salt thereof is released from the tablet at about 4 hoursin the test, and at least about 80%, by weight, of the oxymorphone orsalt thereof is released from the tablet at about 10 hours in the test.55. An analgesically effective controlled release pharmaceuticalcomposition for oral delivery, comprising: a. a controlled releasedelivery system with a release rate profile designed to provide adequateblood plasma levels of oxymorphone and 6-hydroxy-oxymorphone over atleast 12 hours to provide sustained pain relief over this same period;and b. about 5 mg to about 80 mg of oxymorphone or a pharmaceuticallyacceptable salt of oxymorphone, wherein oxymorphone is the sole activeingredient, wherein upon placement of the composition in an in vitrodissolution test comprising USP Paddle Method at 50 rpm in 500 ml mediahaving a pH of 1.2 to 6.8 at 37° C., about 15% to about 50%, by weight,of the oxymorphone or salt thereof is released from the tablet at about1 hour in the test.
 56. The composition of claim 55, wherein upon oraladministration of a single dose of the composition to a human subject,the oxymorphone C_(max) is at least 50% higher when the dose isadministered to the subject under fed as compared to fasted conditions.57. The composition of claim 55, wherein the composition is in the formof a tablet and wherein at least 27%, by weight, of the oxymorphone orsalt thereof is released from the tablet at about 1 hour in the test, atleast 40%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 2 hours in the test, at least 50%, by weight,of the oxymorphone or salt thereof is released from the tablet at about3 hours in the test, at least 64%, by weight, of the oxymorphone or saltthereof is released from the tablet at about 5 hours in the test, atleast 70%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 6 hours in the test, at least 79%, by weight,of the oxymorphone or salt thereof is released from the tablet at about8 hours in the test, at least 85%, by weight, of the oxymorphone or saltthereof is released from the tablet at about 10 hours in the test, andat least 89%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 12 hours in the test.
 58. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 27%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 1 hour in the test.
 59. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 40%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 2 hours in the test.
 60. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 50%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 3 hours in the test.
 61. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 64%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 5 hours in the test.
 62. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 70%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 6 hours in the test.
 63. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 79%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 8 hours in the test.
 64. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 85%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 10 hours in the test.
 65. The composition ofclaim 55, wherein the composition is in the form of a tablet and whereinat least 89%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 12 hours in the test.
 66. An analgesicallyeffective controlled release pharmaceutical composition for oraldelivery, comprising: a. a controlled release delivery system with arelease rate profile designed to provide adequate blood plasma levelsover at least 12 hours to provide sustained pain relief over this sameperiod; and b. about 5 mg to about 80 mg of oxymorphone or apharmaceutically acceptable salt of oxymorphone, wherein oxymorphone isthe sole active ingredient, wherein upon placement of the composition inan in vitro dissolution test comprising USP Paddle Method at 50 rpm in500 ml media having a pH of 1.2 to 6.8 at 37° C., about 15% to about50%, by weight, of the oxymorphone or salt thereof is released from thetablet at about 1 hour in the test, and wherein upon oral administrationof the composition to a human subject, the blood plasma levels ofoxymorphone comprise one or more peaks.
 67. The composition of claim 66wherein the blood plasma levels comprise two peaks.
 68. The compositionof claim 66 wherein upon oral administration of the composition to asubject in need of an analgesic effect: (i) the composition providesdetectable blood plasma levels of 6-OH oxymorphone and oxymorphone; (ii)the blood plasma levels of 6-OH oxymorphone and oxymorphone peak withinabout 1 hour to about 8 hours after administration; and (iii) the bloodplasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio ofarea under the curve (AUC_((0 to inf))) of blood plasma level versustime for 6-OH oxymorphone compared to oxymorphone in a range of about0.5 to about 1.5.
 69. The composition of claim 66 wherein upon oraladministration of the composition to a subject in need of an analgesiceffect the blood plasma levels of oxymorphone exhibit two or three peakswithin about 12 hours after administration.
 70. The composition of claim66 wherein upon oral administration of the composition to a subject inneed of an analgesic effect the blood plasma levels of oxymorphonecomprise a first peak at about 3 hours after administration and a secondpeak at about 6-7 hours after administration.
 71. The composition ofclaim 66 wherein the composition is in the form of a tablet and about45% to about 80%, by weight, of the oxymorphone or salt thereof isreleased from the tablet at about 4 hours in the test, and at leastabout 80%, by weight, of the oxymorphone or salt thereof is releasedfrom the tablet at about 10 hours in the test.
 72. A controlled releasepharmaceutical composition comprising oxymorphone or a pharmaceuticallyacceptable salt thereof as the sole active ingredient and a controlledrelease matrix, comprising about 10% to about 75% (by total weight ofthe controlled release matrix) of a gelling agent which forms a gel uponexposure to gastrointestinal fluid; wherein upon placement of thecomposition in an in vitro dissolution test comprising USP paddle methodat 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37° C., about 15%to about 50%, by weight, of the oxymorphone or salt thereof is releasedfrom the composition after about 1 hour in the test.
 73. Thepharmaceutical composition of claim 72 wherein about 45% to about 80%,by weight, of the oxymorphone or salt thereof is released from thecomposition after about 4 hours in the test.
 74. The pharmaceuticalcomposition of claim 72 wherein at least 80%, by weight, of theoxymorphone or salt thereof is released from the composition after about10 hours in the test.
 75. The pharmaceutical composition of claim 72wherein upon oral administration of the dosage form to a human subjectin need of an analgesic effect, the blood plasma concentration ofoxymorphone comprises one or peaks.
 76. The pharmaceutical compositionof claim 72 wherein upon oral administration of the dosage form to ahuman subject in need of an analgesic effect, the blood plasmaconcentration of oxymorphone comprises a first peak at about 3 hoursafter administration and a second peak at about 6-7 hours afteradministration; and wherein (i) the dosage form provides detectableblood plasma levels of 6-OH oxymorphone and oxymorphone; (ii) the bloodplasma levels of 6-OH oxymorphone and oxymorphone peak within about 1hour to about 8 hours after administration; (iii) the blood plasmalevels of 6-OH oxymorphone and oxymorphone exhibit a ratio of area underthe curve (AUC_((0 to inf))) of blood plasma level versus time for 6-OHoxymorphone compared to oxymorphone in a range of about 0.5 to about1.5; and (iv) the duration of the analgesic effect is through at leastabout 12 hours after administration.
 77. A controlled releasepharmaceutical composition comprising oxymorphone or pharmaceuticallyacceptable salt thereof as the sole active ingredient, and a controlledrelease matrix comprising about 10% to about 75% (by total weight of thecontrolled release matrix) of a gelling agent which forms a gel uponexposure to gastrointestinal fluid; wherein upon placement of thecomposition in an in vitro dissolution test comprising USP paddle methodat 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37° C., about 15%to about 50%, by weight, of the oxymorphone or salt thereof is releasedfrom the composition after about 1 hour in the test, about 45% to about80%, by weight, of the oxymorphone or salt thereof is released from thecomposition after about 4 hours in the test, and at least 80%, byweight, of the oxymorphone or salt thereof is released from thecomposition after about 10 hours in the test, wherein upon oraladministration of a single dose of the composition to a human subject,the composition provides an oxymorphone C_(max) of at least 50% higherwhen the dose is administered to the subject under fed as compared tofasted conditions and provides a difference in oxymorphone AUC_((0-inf))of less than 20% higher when the dose is administered to the subjectunder fed as compared to fasted conditions.
 78. The pharmaceuticalcomposition of claim 77 wherein upon oral administration of the dosageform to a human subject in need of an analgesic effect the blood plasmalevel of oxymorphone displays two or three peaks over about the first 12hours after administration; and (i) the dosage form provides detectableblood plasma levels of 6-OH oxymorphone and oxymorphone; (ii) the bloodplasma levels of 6-OH oxymorphone and oxymorphone peak within about 1hour to about 8 hours after administration; (iii) the blood plasmalevels of 6-OH oxymorphone and oxymorphone exhibit a ratio of area underthe curve (AUC_((0 to inf))) of blood plasma level versus time for 6-OHoxymorphone compared to oxymorphone in a range of about 0.5 to about1.5; and (iv) the duration of the analgesic effect is through at leastabout 12 hours after administration.
 79. The pharmaceutical compositionof claim 77 wherein about 58% to about 66%, by weight, of theoxymorphone or salt thereof is released from the composition after about4 hours in the test.
 80. The pharmaceutical composition of claim 77wherein about 85% to about 96%, by weight, of the oxymorphone or saltthereof is released from the composition after about 10 hours in thetest.
 81. A method of treating pain in a subject in need thereof, themethod comprising administering to the subject the pharmaceuticalcomposition of claim 72 in an amount sufficient to provide the subjectwith about 5 mg to about 80 mg of oxymorphone or salt thereof, whereinupon oral administration of a single dose of the composition to a humansubject, the composition provides an oxymorphone C_(max) of at least 50%higher when the dose is administered to the subject under fed ascompared to fasted conditions and provides a difference in oxymorphoneAUC_((0-inf)) of less than 20% higher when the dose is administered tothe subject under fed as compared to fasted conditions.
 82. A method oftreating pain in a subject in need thereof, the method comprisingadministering to the subject the pharmaceutical composition of claim 77in an amount sufficient to provide the subject with about 5 mg to about80 mg of oxymorphone or salt thereof.